miR-431在耳聋发病中的作用及分子机制

目前已有众多研究证实miRNAs对听觉系统的发生和功能的稳定起重要作用。但缺少合适的动物模型一直是miRNA与耳聋发病机制研究的瓶颈之一。本课题组在前期研究中鉴定了一个在耳蜗中高丰度表达的miRNA—miR-431，采用转基因小鼠的研究发现过表达miR-431的小鼠存在听力损失。miR-431转基因小鼠是已有报道中第二个miRNA相关听力损失动物模型。进一步的分子机制研究发现miR-431可能通过靶向Eya4调控内耳功能。miRNA与mRNA的不完全形式结合导致其对器官发育和疾病发生的调控通常是通过多个靶基因的协同作用来实现的。因此，在前期工作基础上，我们提出本课题的核心研究内容是：采用miR-431转基因小鼠进一步确定耳聋表型，利用RNA深度测序联合生物信息学分析筛选miR-431调控的靶基因，以期初步构建miR-431及其靶基因的耳聋相关调控网络。

Many studies have shown that miRNAs are essential for the development and function of auditory system. But lacking of suitable animal models have been one of the bottlenecks in study of the pathogenesis of miRNA and deafness. In the preliminary study, a high-abundance expression of miRNA-miR-431 was identified in the cochlea. Using miR-431 over-expression transgenic mice, we discovered that auditory brain stem response thresholds were significantly higher in transgenic mice than in wildtype mice. MiR-431 transgenic mice are the second miRNA-related hearing loss animal models reported. Further molecular mechanism studies showed that miR-431 might involve in regulating inner ear function by targeting Eya4. MiRNAs usually target to multiple genes to make a synergistic effects on regulation of organ development and disease progression, because of the incomplete forms of combination between miRNAs and mRNAs. Therefore, on the basis of the previous work, we plan to make further determination of the deafness phenotype of miR-431 transgenic mice. And we will use RNA deep sequencing and bioinformatics analysis to screen out the target gene regulated by miR-431 and construct the regulatory network.